Trypanosomiasis includes African sleeping sickness which is prevalent in Africa, and Chagas disease which is prevalent in South America. Trypanosomiasis that is called as African sleeping sickness or as human African trypanosomiasis is a reemerging protozoan infectious disease and number of people infected is estimated to be 18.3 million or more in a year and number of people died from said disease is considered to be about 50,000 in a year. Particularly, trypanosoma protozoa that are parasitic in humans are classified into two types, i.e., Trypanosoma brucei gambiense and T. b. rhodesiens, the former causes chronic sleeping sickness and the latter causes acute sleeping sickness. Trypanosomiasis is infectious disease with high mortality. In the last stage of infection, trypanosoma protozoa migrate into the central nervous system, and 80% or more of infected patients fall into a coma and eventually die. These trypanosoma protozoa are transmitted by tsetse fly which inhabits only Africa.
Trypanosoma brucei gambiense (T. b. gambiense) and Trypanosoma brucei rhodesiens (T. b. rhodesiens) are zoonotic parasitic species, which can parasitize farm animals such as cows, horses and sheep as well as wild animals such as gazelles and gnus. These animals serve as reservoir hosts, while they themselves do not develop trypanosomiasis. Further, another trypanosoma protozoa parasitize farm animals but not humans, that include, for example, T. brucei brucei (nagana) which belongs to the subgenus Trypanosoma and T. vivax vivax (souma) which belongs to the subgenus Duttonella, and animals infected with these protozoa follow a lethal course of infection depending on the animal species. These protozoa are also transmitted by tsetse fly.
Tsetse flies live in a region over 1,000 square km extended from the East coast to the West coast of the sub-Saharan African continent across 36 countries. Currently 150 million or more farm animals are exposed to the threat of said trypanosomiases. Moreover, there are non-tsetse fly-mediated trypanosoma protozoa that infect animals via, for example, mechanical transmission by blood-sucking insects such as horse fly and stable fly, which include T. evansi (surra) and T. equiperdum (dourine), both of which are subgenus Trypanosoma. Particularly, surra has developed into a pandemic spreading over Africa, Latin America, Southeast Asia, China, Middle East, India, and other regions. Recently, surra tends to become epidemic spread, making surra the most alarming animal trypanosomiasis in invasion of Japan.
Existing anti human-infectious trypanosoma agents against these trypanosoma protozoa, including classic drugs such as suramin (developed in 1923), pentamidine (developed in 1939) and melarsoprol (developed in 1953) as well as chemically-synthesized pharmaceutical products such as eflornithine (developed in 1978) have been used for long time, during the last half-century. Although suramin is effective in the initial stage of infection with T. b. gambiense and T. b. rhodesiens, it is nephrotoxic.
Pentamidine is effective in the initial stage of infection with T. b. gambiense, but is ineffective for T. b. rhodesiens. Moreover, pentamidine has side effects such as hypotension and reduction in blood glucose. Melarsoprol, an arsenical agent, exerts an effect in the terminal stage of infection with T. b. gambiense and T. b. rhodesiens (central neuropathy) due to its penetration of the blood brain barrier. However, it causes encephalopathy because of its strong side effects on the central nervous system. Further, melarsoprol-resistant protozoan strain has emerged.
Eflornithine also penetrates the blood brain barrier and exerts an effect in the terminal stage of infection with melarsoprol-resistant T. b. gambiense, for which melarsoprol is ineffective. However, it is ineffective for T. b. rhodesiens. Moreover, these drugs has been used for a long time, which brings less effectiveness of said drugs gradually. Similarly, animal trypanosomiasis has been treated with drugs such as diminazene, suramin, isometamidium and a mutagenic substance homidium. Since these drugs have particularly used for a long period, until now protozoa resistant to these drugs have emerged in various regions. Thus posed drastic decrease of the utility of said drugs for treatment of trypanosomiasis become a major problem.
Due to a delay of the development of a new drug, classic existing drugs with strong side effects are still used for the treatment of African sleeping sickness now. Therefore, development of novel and effective drugs for trypanosomiasis in humans and in animals are demanded on a worldwide scale. In addition, as described above, the existing anti human-infectious trypanosoma agents are differentially-effective depending on the kind of protozoa and the stage of infection, and are not effective against drug resistant protozoan strains. It is desired to develop an anti-trypanosoma agent which is irrespective of the kind of trypanosoma protozoa and of the stage of infection, particularly an anti-trypanosoma agent which is specifically effective against T. b. rhodesiens and in the terminal stage of infection (for central neuropathy), having a novel skeleton with reduced side effects.
In order to solve the aforementioned problems, therapeutic drugs for the treatment of trypanosomiasis have been already reported, but no effective compound has yet been discovered (see Patent Literature 1).